A framework for individualized splice-switching oligonucleotide therapy.

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

Nirmatrelvir Resistance-de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated With Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure-a Case Report.

Resistance of SARS-CoV-2 to antivirals was shown to develop in immunocompromised individuals receiving remdesivir. We describe an immunocompromised patient who was treated with repeated and prolonged courses of nirmatrelvir and developed de-novo E166V/L50F mutations in the Mpro region. These mutations were associated with clinical and virological treatment failure.

Pleuroparenchymal fibroelastosis as a late complication of childhood cancer therapy: A case series.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with distinct clinicopathologic features. It has been associated with exposure to hematopoietic stem cell transplantation (HSCT) and classical alkylating agents. Here, we highlight PPFE as a late complication of childhood cancer therapy by describing the cases of four survivors of childhood cancer with a diagnosis of treatment-related PPFE. All patients received high-dose alkylating agents. PPFE should be considered in the differential diagnosis of restrictive lung disease in patients with history of exposure to alkylating agents or HSCT. Development of PPFE-specific, noninvasive diagnostic tools and disease-modifying therapies will clinically benefit these patients.

Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.

BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown. OBJECTIVE: To determine whether underweight status increases the risk of mortality. PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search. PARTICIPANTS: Childhood cancer five-year survivors diagnosed during 1970-1986 in the Childhood Cancer Survivor Study Exposure: Underweight status, defined as body mass index (BMI) < 18.5 kg/m2 compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m2. MAIN OUTCOMES: Overall mortality and cancer-specific mortality. RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1% vs. 4.5%, p < .01) and participants with younger age at diagnosis (8.2% for < 5 years vs. 6.1% for ≥5 years, p < .01), lower household income (8.9% for < $20,000 vs. 6.0% for ≥ $20,000, p < .01), or a history of serious chronic condition (p = .05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p < .01) for underweight survivors, compared with ideal-weight survivors. CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Ovarian function in female survivors of high-risk neuroblastoma.

INTRODUCTION: Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. METHODS: Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy ± radiation ("non-ASCR") (n = 32) or with chemotherapy ± radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n = 51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. RESULTS: Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p < 0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p = 0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. DISCUSSION: Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.

Do discussions of financial burdens decrease long-term financial toxicity in adolescent and young adult cancer survivors?

PURPOSE: This study aims to evaluate the associations between patient-provider cost discussions with patient-reported out-of-pocket (OOP) spending and long-term financial toxicity (FT) among adolescent and young adult (AYA; 15-39 years old) cancer survivors. METHODS: Using a cross-sectional survey, we assessed the themes and quality of patient discussions with providers about financial needs and general survivorship preparation, quantified patients' levels of FT, and evaluated patient-reported OOP spending. We determined the association between cancer treatment cost discussion and FT using multivariable analysis. In a subset of survivors (n = 18), we conducted qualitative interviews and used thematic analysis to characterize responses. RESULTS: Two hundred forty-seven AYA survivors completed the survey at a mean of 7 years post treatment and with a median COST score of 13. 70% of AYA survivors did not recall having any cost discussion about their cancer treatment with a provider. Having any cost discussion with a provider was associated with decreased FT (ß = 3.00; p = 0.02) but not associated with reduced OOP spending (χ2 = 3.77; p = 0.44). In a second adjusted model, with OOP spending included as a covariate, OOP spending was a significant predictor of FT (ß = - 1.40; p = 0.002). Key qualitative themes included survivors' frustration about the lack of communication related to financial issues throughout treatment and in survivorship, feeling unprepared, and reluctance to seek help. CONCLUSION: AYA patients are not fully informed about the costs of cancer care and FT; the dearth of cost discussions between patients and providers may represent a missed opportunity to reduce costs.

Differential platelet activation through an interaction with spike proteins of different SARS-CoV-2 variants.

COVID-19 disease is associated with an increased risk of thrombotic complications, which contribute to high short-term mortality. Patients with COVID-19 demonstrate enhanced platelet turnover and reactivity, which may have a role in the development of thrombotic events and disease severity. Evidence has suggested direct interaction between SARS-CoV-2 and platelets, resulting in platelets activation. Here, we compare the effect of various SARS-CoV-2 spike variants on platelet activation. Engineered lentiviral particles were pseudotyped with spike SARS-CoV-2 variants and incubated with Platelet Rich Plasma obtained from healthy individuals. The pseudotyped SARS-CoV-2 exhibiting the wild-type Wuhan-Hu spike protein stimulated platelets to increase expression of the surface CD62P and activated αIIbß3 markers by 3.5 ± 1.2 and 3.3 ± 0.7 fold, respectively (P = 0.004 and 0.003). The Delta variant induced much higher levels of platelet activation; CD62P expression was increased by 6.6 ± 2.2 fold and activated αIIbß3 expression was increased by 5.0 ± 1.5 fold (P = 0.005 and 0.026, respectively). The Omicron BA.1 and the Alpha variants induced the lowest level of activation; CD62P expression was increased by 1.7 ± 0.4 and 1.6 ± 0.9 fold, respectively (P = 0.003 and 0.008), and activated αIIbß3 expression by 1.8 ± 1.1 and 1.6 ± 0.8, respectively (P = 0.003 and 0.001). The Omicron BA.2 variant induced an increase of platelets activation comparable to the Wuhan-Hu (2.8 ± 1.2 and 2.1 ± 1.3 fold for CD62P and activated αIIbß3 markers, respectively). The results obtained for various COVID-19 variants are in correlation with the clinical severity and mortality reported for these variants.

Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy: An updated analysis of more than 10 years of follow-up.

BACKGROUND: It is unclear how intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in childhood cancer patients. PROCEDURE: Patients aged ≤21 years treated with IMRT between 1998 and 2009 and who survived ≥5 years after IMRT were included. SMN site in relation to isodose level (IDL) of IMRT was evaluated. Standardized incidence ratios (SIR) and excess absolute risks (EAR) were calculated. Cumulative incidences were estimated with death as a competing risk. RESULTS: Three-hundred twenty-five patients were included with median follow-up of 11.2 years from IMRT (interquartile range: 9.4-14.0) among patients alive at the end of follow-up. Two hundred (62%) patients had ≥10 years of follow-up and 284 (87%) patients were alive at the time of analysis. Fifteen patients developed SMNs (11 solid, four hematologic). Median time from IMRT to solid SMN was 11.0 years (range: 6.8-19.2) with 10- and 15-year cumulative incidences 1.8% (95% CI: 0.7-3.9) and 3.5% (95% CI: 1.4-7.5), respectively; SIR was 13.7 (95% CI: 6.9-24.6) and EAR was 2.8 per 1000 person-years (95% CI: 1.0-4.6). Eight solid SMNs developed within the IMRT field (100% IDL [n = 5], 80% IDL [n = 1], 50% IDL [n = 1], 40% IDL [n = 1]), one within the 70%-80% IDL of a conventional field, one was out-of-field, and one could not be determined. CONCLUSIONS: With median follow-up of >10 years, many solid SMNs after IMRT in childhood cancer survivors develop in the high-dose region. These data serve as a foundation for comparison with other modalities of radiation treatment (e.g., proton therapy).

Economic distress, financial toxicity, and medical cost-coping in young adult cancer survivors during the COVID-19 pandemic: Findings from an online sample.

BACKGROUND: Young adult (YA) cancer survivors are at risk for financial toxicity during and after cancer treatment. Financial toxicity has been associated with medical-related cost-coping behaviors such as skipping or delaying treatment. The coronavirus disease 2019 (COVID-19) pandemic has resulted in dire economic consequences that may worsen financial hardship among young survivors. METHODS: This was a cross-sectional survey; data collection occurred online. A convenience sample was recruited through YA cancer advocacy groups and social media. Negative economic events associated with the COVID-19 pandemic (eg, income loss, increased debt, and decreased job security) and medical-related cost-coping were documented. A validated measure assessed cancer-related financial toxicity. RESULTS: Participants (N = 212) had a mean age of 35.3 years at survey completion and a mean age of 27.4 years at diagnosis. Financial toxicity (mean, 14.0; SD, 9.33) was high. Two-thirds of the sample experienced at least 1 negative economic event during COVID-19, and 71% engaged in at least 1 medical cost-coping behavior. Cost-coping and pandemic-related negative economic events were significantly correlated with cancer-related financial toxicity. In multivariable analyses, pandemic-related negative economic events and financial toxicity were associated with cost-coping. CONCLUSIONS: Acute negative economic events associated with the COVID-19 pandemic may exacerbate cancer-related financial toxicity and overall financial hardship among YAs and lead to cost-coping behaviors that can compromise survivorship care and health outcomes. Multilevel, systematic interventions are needed to address the financial needs of YA survivors after the global pandemic.

COVID-19 in pediatric survivors of childhood cancer and hematopoietic cell transplantation from a single center in New York City.

Childhood cancer survivors are at increased risk for treatment-related late effects; data are lacking on how coronavirus disease 2019 (COVID-19) infection impacts this cohort. We assessed COVID-19-related symptoms, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG seroprevalence, and rate of COVID-19-related hospitalization among 321 asymptomatic survivors of childhood cancer or transplantation seen for routine long-term follow-up between May and September 2020 in a New York City tertiary cancer center. While 10.9% (n = 35) reported possible COVID-19-related symptoms, 7.8% (n = 20) of those tested had positive SARS-CoV-2 IgG, and one patient (0.3%) required COVID-19-related hospitalization. This report suggests that childhood cancer survivors appear to be at relatively low risk for COVID-19 complications.

General cancer screening practices among adult survivors of retinoblastoma: Results from the Retinoblastoma Survivor Study.

We assessed breast, cervical, and colorectal cancer screening practices in adult retinoblastoma (Rb) survivors and non-Rb controls. We found that most Rb survivors adhered to general population cancer screening recommendations. Rates did not differ among Rb survivors and non-Rb controls, or among survivors by laterality, even though bilateral survivors reported higher levels of concern about future health and cancer risk. Older age, being overweight/obese, and lack of recent contact with medical personnel were independently associated with decreased utilization of Pap smear among female Rb survivors. Future studies are warranted to determine whether these associations might provide an opportunity for intervention.

Training in Long-Term Follow-Up: Fellowship in Childhood Cancer Survivorship.

Childhood cancer survivors are a growing population with high morbidity and many healthcare needs. As time from treatment lengthens, these patients are more and more likely to be followed in community primary care. Yet, studies suggest that primary care providers are unprepared (although not unwilling) to care for childhood cancer survivors. The 1-year fellowship in childhood cancer survivorship presented herein represents an educational intervention designed to prepare clinical leaders in survivorship. Ultimately, this effort may help address current gaps in care for childhood cancer survivors.

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.

BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma.

PURPOSE: To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. PARTICIPANTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm. RESULTS: Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Whole-body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and young adult survivors of germline retinoblastoma: An update.

BACKGROUND: Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. PROCEDURE: WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. RESULTS: Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). CONCLUSIONS: Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.

Outcomes of routine upper gastrointestinal series screening and surveillance after laparoscopic adjustable gastric banding.

BACKGROUND: Esophageal dilatation and dysmotility are known complications of the laparoscopic adjustable gastric band (LAGB), but their incidence varies widely in the literature. There are no formal recommendations guiding surveillance for these potentially underdiagnosed pathologies. This study demonstrates the utility and outcomes of a yearly upper gastrointestinal series screening protocol to detect and manage esophageal dysfunction after LAGB. METHODS: We reviewed charts for all patients presenting for an outpatient surgical encounter related to LAGB between January 1, 2015 and December 31, 2017. Exclusion criteria included failure to undergo UGIS 6 months or more after band placement, or having undergone band placement in combination with another bariatric procedure. Descriptive statistics were used to characterize demographics, imaging findings and surgical outcomes. All imaging classifications were based on final radiologist report. Means were compared using a Student's t test. RESULTS: A total of 322 records were reviewed with 39 patients excluded; 31 without UGIS and 8 with concomitant gastric bypass. 85% were female with an average age of 50 years. 66.8% identified as white or Caucasian with 24.7% black/African-American. Greater than 75% of the cohort had at least 5-year follow-up interval. UGIS was performed for symptoms in 66.1% and for routine screening in 33.9%. Of asymptomatic patients, 47.9% demonstrated esophageal dilatation or dysmotility on UGIS, similar to 51.3% of symptomatic patients. 96.8% of all patients went on to band removal. Sixty-four patients had repeat UGIS an average of 8 months following band removal, of which 40.6% were persistently abnormal. CONCLUSIONS: The incidence of esophageal pathology was significantly higher than most reported series, as was the number of patients with persistently abnormal UGIS despite band removal. The data supports our policy of yearly UGIS for all post-LAGB patients, with strong recommendation for band removal if esophageal dilatation or dysmotility is found.

Impact of enucleation on adult retinoblastoma survivors' quality of life: A qualitative study of survivors' perspectives.

OBJECTIVES: Retinoblastoma is the most common primary intraocular tumor of childhood with >95% survival rates in the US. Traditional therapy for retinoblastoma often included enucleation (removal of the eye). While much is known about the visual, physical, and cognitive ramifications of enucleation, data are lacking about survivors' perception of how this treatment impacts overall quality of life. METHODS: Qualitative analysis of an open-ended response describing how much the removal of an eye had affected retinoblastoma survivors' lives and in what ways in free text, narrative form. RESULTS: Four hundred and four retinoblastoma survivors who had undergone enucleation (bilateral disease = 214; 52% female; mean age = 44, SD = 11) completed the survey. Survivors reported physical problems (n = 205, 50.7%), intrapersonal problems (n = 77, 19.1%), social and relational problems (n = 98, 24.3%), and affective problems (n = 34, 8.4%) at a mean of 42 years after diagnosis. Three key themes emerged from survivors' responses; specifically, they (1) continue to report physical and intrapersonal struggles with appearance and related self-consciousness due to appearance; (2) have multiple social and relational problems, with teasing and bullying being prominent problems; and (3) reported utilization of active coping strategies, including developing more acceptance and learning compensatory skills around activities of daily living. SIGNIFICANCE OF RESULTS: This study suggests that adult retinoblastoma survivors treated with enucleation continue to struggle with a unique set of psychosocial problems. Future interventions can be designed to teach survivors more active coping skills (e.g., for appearance-related issues, vision-related issues, and teasing/bullying) to optimize survivors' long-term quality of life.

A novel miniature transposon-like element discovered in the coding sequence of a gene that encodes for 5-formyltetrahydrofolate in wheat.

BACKGROUND: Transposable elements (TEs) comprise over 80% of the wheat genome and usually possess unique features for specific super-families and families. However, the role of TEs in wheat evolution and reshaping the wheat genome remains largely unclear. RESULTS: In this study, we discovered a miniature (307 bp in length) TE-like sequence in exon 6 of a gene that encodes for 5-formyltetrahydrofolate, in two accessions of wild emmer wheat (T. turgidum ssp. dicoccoides) and has interfered with the gene translation by creating a shorter reading frame as a result of a stop codon. The sequence that was termed Mariam, does not show any structural similarity to known TEs. It does not possess terminal inverted repeats (TIRs) that would allow us to assign this element to one of the TIR DNA super-families, and it does not possess characteristic features of SINE, such as a Pol-III promotor or a poly-A tail. In-silico analysis of five publicly available genome drafts of Triticum and Aegilops species revealed that Mariam element appears in a very low copy number (1-3 insertions) in diploid wheat species and ~ 12 insertions in tetraploid and hexaploidy wheat species. In addition, Mariam element was found to be unique to wheat, as it was not found in other plant genomes. The dynamic nature of Mariam in the wheat genome was assessed by site-specific PCR analysis and revealed that it retained activity in wild emmer populations in a population-specific manner. CONCLUSIONS: This study provides additional insight into the evolutionary impact of TEs in wheat.

Content review of pediatric ethics consultations at a cancer center.

BACKGROUND/OBJECTIVES: Ethical challenges in pediatric oncology arise at every stage of illness. However, there are sparse data on the content of and reason for ethics consultations in the field. We sought to evaluate the content and characteristics of ethics consultations in pediatric patients at a cancer center. DESIGN/METHODS: We retrospectively identified ethics consultations performed for patients diagnosed with cancer at ≤21 years of age who were treated in the Department of Pediatrics from 2007 to 2017. Using an established coding schema, two independent reviewers analyzed the content of ethics consultation notes and identified core ethical issues and relevant contextual issues. Demographic, clinical, and consultation-specific data were also collected. RESULTS: Thirty-five consultations were performed for 32 unique patients. The most commonly identified ethical issues were obligation to provide nonbeneficial treatment (29%) and resuscitation preferences (26%). Communication conflicts were the most commonly identified contextual issue (40%). There were two themes that emerged repeatedly but were not a part of the original coding schema-four consultations (11%) that involved physicians questioning their obligation to provide potentially toxic treatment in the setting of poor patient/parent compliance, and two consultations (6%) related to complex risk-benefit analysis in the setting of an invasive procedure with uncertain benefit. CONCLUSIONS: Pediatric ethics consultations are infrequent at this specialty cancer hospital. Ethical issues focused on treatment and end-of-life care and included a diversity of communication conflicts.

Assessment of pulmonary outcomes, exercise capacity, and longitudinal changes in lung function in pediatric survivors of high-risk neuroblastoma.

BACKGROUND/OBJECTIVES: Survivors of high-risk neuroblastoma (NB) are exposed to multimodality therapies early in life and confront late therapy-related toxicities. This study assessed respiratory symptoms, exercise capacity, and longitudinal changes in pulmonary function tests (PFTs) among survivors. DESIGN/METHODS: Survivors of high-risk NB followed in the long-term follow-up clinic at Memorial Sloan Kettering Cancer Center were enrolled. Symptom and physical activity questionnaires were completed. Medical records were reviewed for treatments and comorbidities. Participants completed spirometry, plethysmography, diffusion capacity of the lung for carbon monoxide, 6-minute walk tests (6MWTs), and cardiopulmonary exercise testing. Questionnaires and PFTs were repeated at least one year after enrollment. RESULTS: Sixty-two survivors participated (median age at study: 10.92 years; median age at diagnosis: 2.75 years; median time since completion of therapy: 5.29 years). Thirty-two percent had chronic respiratory symptoms. Seventy-seven percent had PFT abnormalities, mostly mild to moderate severity. Thirty-three completed 6MWTs (median, 634.3 meters); eight completed cardiopulmonary exercise tests (mean VO2 max: 63% predicted); 23 completed a second PFT revealing declines over a median 2.97 years (mean percent predicted forced vital capacity: 79.9 to 70.0; mean forced expiratory volume in 1 second: 81.6 to 69.9). Risks for abnormalities included thoracic surgery, chest radiation therapy (RT), thoracic surgery plus chest RT, and hematopoietic stem cell transplant. CONCLUSIONS: In this cohort of survivors of high-risk NB, PFT abnormalities were common but mostly mild or moderate. Maximal exercise capacity may be affected by respiratory limitations and declines in lung function may occur over time. Continued pulmonary surveillance of this at-risk population is warranted.